PROJECT SUMMARY/ABSTRACT We are proposing a seamless phase 2A-B Proof of Concept (POC) trial of PQ 912, a first-in-class small molecule treatment for early Alzheimer?s disease (AD) with a unique mechanism of action. PQ 912 inhibits the enzyme glutaminyl cyclase (QC) and its isozyme iso-QC, resulting in reduced levels of pGlu-A?, a post- translationally modified form of A? (Glutamate 3/11 cyclization), as well as pGlu-CCL2, a post-translationally modified form of cytokine monocyte chemoattractant protein 1 (CCL2) (Glutamine cyclisation). These proteins are significantly overexpressed in AD where pGlu-A? has been shown to be synaptotoxic, proinflammatory, promoting of self-aggregation into oligomers, and resistant to degradation, while pGlu-CCL2 has been linked to the presence and severity of neuroinflammation. In preclinical models, these toxic effects can be attenuated with PQ 912 treatment. PQ 912 has completed extensive preclinical AD testing, a large phase 1 program exploring its dose range with PK PD testing, and an early phase 2A clinical trial. It is an excellent candidate to take into further development, as it can address a set of stringent POC criteria including target validation, suitable dose range for testing with direct PK PD measurement, with biomarkers that can evaluate relevant downstream biological effects. Phase 2A positive results on quantitative EEG with effects on theta power and on CSF biomarkers including YKL 40 also support further development. Based on these aggregate results, our proposed clinical study targets early AD with the goal of improving cognition and everyday function through improved synaptic function, and attenuating longer term disease progression through its dual pathways of PQ 912?s mode of action. The first phase of the trial, phase 2A, uses a group sequential dose design to find the highest well tolerated and safe dose of PQ 912 to take through to phase 2B, a 72-week safety and efficacy study. A planned interim futility analysis will be conducted at week 52. The primary efficacy outcome measure is Clinical Dementia Rating ? Sum of Boxes, and a key secondary outcome is a novel cognitive-functional composite shown previously to be highly sensitive to change in MCI and early AD in the Alzheimer?s Disease Neuroimaging Initiative (ADNI). Additional secondary endpoints include measurement of QC inhibition and target occupancy in CSF, quantitative EEG with spectral analysis of theta power, ADAS-Cog 13, selected measures from the ADNI neuropsychological test battery, Functional Activities Questionnaire, and the Neuropsychiatric Inventory. Safety including SAEs, AEs, DAE-Is and other safety monitoring will be followed throughout with oversight of participant safety from the DSMB. In summary, this trial will evaluate a novel treatment for early AD that has potential for both symptomatic and disease-modifying effects while simultaneously validating novel composite outcome measures within a trial setting.